Cannabinoids are compounds found in Cannabis sativa (also know as marijuana) with cannabinol, cannabidiol and Δ9-tetrahydrocannabinol (Δ9-THC) being the most representative molecules. The therapeutic usage of Cannabis can be dated back to ancient dynasties of China and includes applications for various illnesses ranging from lack of appetite, emesis, cramps, menstrual pain, spasticity to rheumatism. The long history of Cannabis use has led to the development of several pharmaceutical drugs. For example, Marinol and Cesamet which are based on Δ9-THC and its analogous nabilone, respectively, are used as anti-emetic and appetite stimulant. Despite of the clinical benefits, the therapeutic usage of Cannabis is limited by its psychoactive effects including hallucination, addiction and dependence.
The effects of Δ9-THC are mediated by at least two G-protein coupled receptors, CB1 and CB2 receptors. CB1 receptors are expressed primarily in the central nervous system, specifically in the cerebral cortex, hippocampus, basal ganglia and cerebellum. These receptors are also found in the reproductive system and in other peripheral tissues including that of the immune system, but to a lesser degree. CB1 receptors regulate the release of neurotransmitters from the pre-synaptic neurons and are believed to mediate most of the euphoric and other central nervous system effects of Δ9-THC.
CB2 receptors are widely expressed in different tissues, primarily in the immune system, with the greatest density in the spleen. The expression level of CB2 in the immune cells is about 10 to 100 times higher than CB1. Within the immune system, CB2 is found in various cell types, including B cells, NK cells, monocytes, microglial cells, neutrophils, T cells, dendritic cells and mast cells. CB2 selective ligands have been developed and tested for their effects in various inflammatory settings. The results have indicated that CB2 receptor modulators can be employed for the treatment of medical conditions having an inflammatory component.
In addition to inflammation, modulation of CB2 receptor activity has been shown to be involved in the pathophysiology of different diseases, including osteoporosis, atherosclerosis, chronic pain, and cancer.
CB2 receptors are largely absent in the central nervous system (CNS) of adult mammals under normal conditions. The expression of CB2 receptors in the fully matured brain is about 1.5% of the level in the spleen, and these receptors are present on neuronal cells, mainly in the cerebellum and in the brain stem. However, CB2 receptors appear to be upregulated in microglial cells and astrocytes under selected neuroinflammatory stimulation.
4′-O-Methylhonokiol
Honokiol, magnolol and 4′-O-methylhonokiol belong to a class of neolignan biphenols. These compounds are isolated from the barks, seed cones, and leaves of trees belonging to the genus Magnolia. In China, Korea, and Japan extracts from the bark or seed cones of the Magnolia tree have been widely used in traditional medicine as analgesic and to treat anxiety and mood disorders. During the last decades, honokiol has been shown to be a pleotropic compound exhibiting not only analgesic, anxiolytic, and antidepressant effects, but also antiemetic, anti-inflammatory, antibacterial, anti-tumorigenic, antithrombotic, neuroprotective, neurotrophic, and serotonergic effects.
The biphenyl neolignan 4′-O-methylhonokiol (MH) isolated from Magnolia grandiflora L. seeds is a potent CB2 receptor ligand (Ki=50 nM), showing a unique inverse agonism and partial agonism via different pathways (cAMP and Ca2+, respectively) and potently inhibits osteoclastogenesis (Schuehly et al., Chem. & Biol. 18: 1053-1064, 2011). MH further attenuates memory impairment in presenilin 2 mutant mice through reduction of oxidative damage and inactivation of astrocytes and the ERK pathway. In a mouse model of Alzheimer's disease (AD), the orally administered MH has been shown to prevent amyloidogenesis and progression of AD by inhibiting neuroinflammation (Lee et al., J. Neuroinflamm. 9:35, 2012). It was postulated that MH may exert its beneficial effects in the AD mouse model via modulation of CB2 receptors expressed in microglial cells and astrocytes (Gertsch and Anavi-Goffer et al., J. Neuroinflamm 9:135, 2012).
Psychiatric Disorders: ADHD/ADD, OCD and TS
Attention Deficit Hyperactivity Disorder (ADHD) which also includes Attention Deficit Disorder (ADD) is a common psychiatric disorder, estimated as affecting 3-9% of school-aged children and young people and 2% of adults worldwide. In addition, in 90% of Tourette's Syndrome (TS) children, the tics exist in conjunction with another disorder, most frequently with ADHD/ADD and/or with OCD.
The cause of most cases of ADHD is unknown but it is believed to involve interactions between genetic and environmental factors. Typically a number of genes are involved, many of which directly affect dopamine neurotransmission. Environmental factors are believed to play a lesser role. Certain cases have been related to previous infection of or trauma to the brain. Very low birth weight, premature birth and early adversity also increase the risk as do infections during pregnancy, at birth, and in early childhood. At least 30% of children with a traumatic brain injury later develop ADHD and about 5% of cases are due to brain damage.
ADHD/ADD is believed to be linked to sub-performance of the dopamine and norepinephrine functions in the brain. The ‘dopamine theory’ of the origin of ADHD/ADD therefore provides the basis for the most common pharmaceutical treatment using methylphenidate. Methylphenidate is a dopamine reuptake inhibitor and also a much weaker norepinephrine reuptake inhibitor, which increases the levels of these neurotransmitters in the brain. However, up to 30% of subjects suffering from ADHD/ADD do not respond to methylphenidate, suggesting that other mechanisms may also be important. Additionally, methylphenidate has been shown to produce side effects, including increased blood pressure, cardiac arrhythmia, loss of appetite, insomnia and psychosis.
Other known classes of drugs for treatment of ADHD/ADD include the noradrenalin reuptake inhibitor atomoxetine that may increase obsessive behavior and blood pressure, and amphetamines that are known to be addictive.
Obsessive Compulsive Disorder (OCD), a type of anxiety disorder, is a potentially disabling illness that traps sufferers in endless cycles of repetitive thoughts and behaviors. Subjects suffering from OCD are plagued by recurring, distressing and uncontrollable thoughts, fears, or images (obsessions). The resulting anxiety leads to an urgent need to perform certain rituals or routines (compulsions). The compulsions are performed in an attempt to prevent or get rid of the obsessive thoughts. Although the compulsions may temporarily alleviate anxiety, the person must perform the compulsions again when the obsessive thoughts return. This OCD cycle can progress to the point of taking up hours of the person's day and significantly interfering with normal activities.
OCD has been linked to abnormalities with the neurotransmitter serotonin, although it could be either a cause or an effect of these abnormalities. It is hypothesized that the serotonin receptors of OCD sufferers may be relatively understimulated. This suggestion is consistent with the observation that many OCD patients benefit from the use of selective serotonin reuptake inhibitors (SSRIs), a class of antidepressant medications that allow for more serotonin to be readily available to other nerve cells.
Tourette's syndrome (TS) is an inherited neuropsychiatric disorder with onset in childhood, characterized by multiple physical (motor) tics and at least one vocal (phonic) tic. Between 0.4% and 3.8% of children ages 5 to 18 may have TS; the prevalence of other tic disorders in school-age children is higher, with the more common tics of eye blinking, coughing, throat clearing, sniffing, and facial movements. Extreme TS in adulthood is a rarity, and Tourette's does not adversely affect intelligence or life expectancy.
The exact cause of Tourette's syndrome is unknown but it is well established that both genetic and environmental factors are involved. The medication with the most proven efficacy in treating tics includes typical and atypical neuroleptics including risperidone (Risperdal®), which can have long-term and short-term adverse effects. The antihypertensive agents clonidine and guanfacine are also used to treat tics showing variable efficacy but a lower side effect profile than the neuroleptics. Stimulants and other medications may be useful in treating ADHD when it co-occurs with tic disorders. Drugs from several other classes of medications can be used when stimulant trials fail, including atomoxetine and tricyclic antidepressants. SSRIs may be prescribed when a Tourette's patient also has symptoms of OCD.
U.S. Patent Application Publication No. 2006/0172019 discloses cannabinoid (CB) receptor inverse agonists and neutral antagonists, and especially CB1 and CB2 inverse agonists and neutral antagonists, such as certain pyrazole compounds, and their use in the inhibition of osteoclasts and/or in the inhibition of bone resorption. U.S. 2006/0172019 further discloses use of CB1 and CB2 inverse agonists and neutral antagonists in treating bone disorders such as osteoporosis, cancer associated bone disorders, and Paget's disease of bone.
U.S. Patent Application Publication No. 2007/0191340 discloses compounds which bind to and are agonists, antagonists or inverse agonists of the CB2 receptor. U.S. 2007/0191340 further discloses methods and pharmaceutical compositions for treating inflammation by way of administration of these compounds as well as methods for treating pain by way of administration of a subset of these compounds, i.e., CB2 agonists.
U.S. Patent Application Publication No. 2008/0194656 discloses benzotriazole derivatives which are potent CB1 modulators, known as antagonists or inverse agonists, useful in the treatment of obesity, psychiatric and neurological disorders.
U.S. Pat. No. 6,864,291 discloses novel pharmaceutical compositions comprising as the active ingredient 4-phenyl pinene derivatives which are specific for the peripheral cannabinoid receptors, including the compound designated HU-308. In particular, the compounds bind efficiently to CB2 but do not bind to CB1. The compounds show no activity in behavioral tests in mice which together have been shown to be specific for tetrahydrocannabinol (THC)-type activity.
U.S. Pat. No. 8,604,087 discloses a composition for treating or preventing amyloid-related disease which includes 4-O-methylhonokiol as an active ingredient. Among the diseases, Alzheimer's disease, cognitive disorder, defective memory, and amyloidosis are listed.
WO 2012/102562 discloses compositions containing a methylhonokiol derivative to suppress beta-amyloid aggregation, beta-secretase activation, and neural cell apoptosis. WO 2012/102562 further discloses pharmaceutical compositions and food compositions for preventing or treating dementia which contain a methylhonokiol derivative.
WO 2012/102560 discloses a 4-O-methylhonokiol derivative having anti-inflammation activity by restraining activation of cyclooxygenase-2, thereby capable of being used for treating various inflammations.
There is an unmet need for improved methods for treating psychiatric disorders including ADHD, tic disorders and/or OCD, which methods show higher curability and have fewer or no side effects.